HIV infection of the central nervous system (CNS) represents an important challenge for both the treatment of neurocognitive disorders as well as the eradication of HIV infection from CNS reservoirs. The eradication of CNS reservoirs of infection will likely be beneficial, not only for treating cognitive dysfunction, but also for treament of HIV infection overall. It is clear that neurocognitive impairment is a negative predictor of survival in HIV infection, suggesting common mechanisms of viral persistence and/or pathogenesis promote both immune deficiency and neurocognitive impairment. At the intersection of both these disorders is the macrophage, where altered immune polarization can suppress antiviral immune reactions and at the same time, serve as a reservoir for viral infection in the CNS, as well as a source of inflammation and neuronal injury. This proposal is a result of a joint interactions between two NIMH supported NeuroAIDS related Centers (P30s) at Temple University (Comprehensive NeuroAIDS Center, Kamel Khalili, Ph.D., Program Director) and UPenn/Children's Hospital (Penn Mental Health Research Center, Dwight Evans, M.D., Program Director). Discussions between CHOP/UPENN and Temple investigators including Jay Rappaport, Ph.D. (Temple University), Tracy Fischer-Smith, Ph.D. (Temple University), and Steven D. Douglas, M.D., with the further interactions with Mark G. Lewis, Ph.D., Bioqual, have led to the conception of an interdisciplinary and translational program project application, investigating therapeutic approaches to eradicating HIV infected reservoirs in the CNS. The application is a multiple PI submission: Jay Rappaport, Ph.D. (Corresponding PI, Temple University) and Steven D. Douglas, M.D. (PI-Children's Hospital). This program project in response to PAR-13-267 (Novel NeuroAIDS Therapeutics, Integrated Preclinical/Clinical Program (PO1), entitled NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS, brings together three projects and three scientific cores, housed at three institutions. These institutions include Temple University School of Medicine, Philadelphia, PA, (Project1, Project 2, Core A and Core B), Children's Hospital of Philadelphia (Project 3 and Co-PI Core A), Bioqual Inc., Rockville, MD (Core C). There are a number of important converging concepts in each of the Projects within this program, which support the overarching hypothesis put forth in this program, that altered immune polarization of the monocyte/macrophage lineage promotes immune dysfunction and the persistence of HIV infection in the CNS and the periphery. A critical concept is the importance of interaction between the CNS and the periphery in HIV infection leading to CNS disease. These processes are centered, to a large degree, on alterations within the myeloid lineage, including peripheral monocytes, tissue macrophages, and microglia. In order to eradicate reservoirs of HIV infection, we propose the intervention within three pathways that contribute to the immune polarization of the myeloid lineage. These three approaches target the following pathways: 1) ATP hydrolysis, where the end product, adenosine, is immune suppressive (Project 1, Jay Rappaport, Ph.D., Project Leader, Temple University), 2) cFMS signaling, where M-CSF and IL-34 ligands for this receptor may contribute to abnormal monocyte/macrophage homeostasis, immune polarization, and survival of infected reservoirs, (Project 2, Tracy Fischer-Smith, Ph.D., Project Leader, Temple University) and 3) neurokinin-1 receptor signaling, where the ligand substance P appears to promote virus infection, immune polarization, survival, and CNS invasion of monocytes/macrophages and the establishment of CNS inflammatory and persistent reservoirs (Project 3, Steven D. Douglas, M.D., Project Leader, Children's Hospital of Philadelphia/UPENN). In the studies proposed in this highly integrated program project, we investigate therapeutic approaches targeting each of these pathways in studies, in vitro, ex vivo, and finally in SIV infected rhesus macaques, alone, in combination, and in the context of cART therapy. The goals and objectives of these projects are supported by an Administrative Core (Core A; Jay Rappaport, Ph.D. and Douglas, M.D., Core Co-Leaders), an Immunopathology Core (Core B; Tracy Fischer-Smith, Ph.D., Core Leader, Temple University), as well as a Non Human Primate Core (Core C; Mark G. Lewis, Ph.D., Bioqual, Inc.). It is anticipated that successful completion of the objectives of this overll program, will make important contributions toward the treatment of HIV infection and eradication of HIV reservoirs, including the CNS. It is anticipated that advances made here with further inform efforts aimed at preventive and therapeutic vaccines, where post-exposure adjuvant approaches could be employed to reactivate otherwise suppressed immune reactions.